HUE035590T2 - Ghrelin O-acyl transferase inhibitory substituted piperidyl ethylpyrimidines - Google Patents

Ghrelin O-acyl transferase inhibitory substituted piperidyl ethylpyrimidines Download PDF

Info

Publication number: HUE035590T2
Authority: HU; Hungary
Prior art keywords: compound; ghrelin; ethyl; add; mmol
Prior art date: 2013-11-14

Application number

HUE14802755A

Other languages

English (en)

Hungarian (hu)

Inventor

Maria Angeles Martinez-Grau

Original Assignee

Lilly Co Eli

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2013-11-14

Filing date

2014-11-06

Publication date

2018-05-28

2014-11-06 Application filed by Lilly Co Eli filed Critical Lilly Co Eli

2018-05-28 Publication of HUE035590T2 publication Critical patent/HUE035590T2/en

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OZVCZTSNWCUNQA-UHFFFAOYSA-N 2-ethyl-4-piperidin-1-ylpyrimidine Chemical class CCC1=NC=CC(N2CCCCC2)=N1 OZVCZTSNWCUNQA-UHFFFAOYSA-N 0.000 title 1
229940123845 Ghrelin O-acyltransferase inhibitor Drugs 0.000 title 1
150000001875 compounds Chemical class 0.000 claims description 72
239000000203 mixture Substances 0.000 claims description 37
150000003839 salts Chemical class 0.000 claims description 28
208000008589 Obesity Diseases 0.000 claims description 15
235000020824 obesity Nutrition 0.000 claims description 14
238000011282 treatment Methods 0.000 claims description 13
239000003112 inhibitor Substances 0.000 claims description 9
239000003795 chemical substances by application Substances 0.000 claims description 7
239000003814 drug Substances 0.000 claims description 6
239000003085 diluting agent Substances 0.000 claims description 4
229940124597 therapeutic agent Drugs 0.000 claims description 3
210000002784 stomach Anatomy 0.000 claims description 2
239000003349 gelling agent Substances 0.000 claims 2
239000000126 substance Substances 0.000 claims 2
AGVBXKRKRXYMBC-UHFFFAOYSA-N 2-(2-piperidin-1-ylethyl)pyrimidine Chemical class N1=C(N=CC=C1)CCN1CCCCC1 AGVBXKRKRXYMBC-UHFFFAOYSA-N 0.000 claims 1
241000385223 Villosa iris Species 0.000 claims 1
WYTGDNHDOZPMIW-RCBQFDQVSA-N alstonine Natural products C1=CC2=C3C=CC=CC3=NC2=C2N1C[C@H]1[C@H](C)OC=C(C(=O)OC)[C@H]1C2 WYTGDNHDOZPMIW-RCBQFDQVSA-N 0.000 claims 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 41
108700013122 acyl-ghrelin Proteins 0.000 description 31
BGHSOEHUOOAYMY-JTZMCQEISA-N ghrelin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)CN)C1=CC=CC=C1 BGHSOEHUOOAYMY-JTZMCQEISA-N 0.000 description 27
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
101710205760 Ghrelin O-acyltransferase Proteins 0.000 description 26
239000007787 solid Substances 0.000 description 25
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
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102100038752 Ghrelin O-acyltransferase Human genes 0.000 description 23
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RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
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Classifications

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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

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Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
Medicinal Chemistry (AREA)
Animal Behavior & Ethology (AREA)
Life Sciences & Earth Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Diabetes (AREA)
Bioinformatics & Cheminformatics (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Engineering & Computer Science (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Epidemiology (AREA)
Obesity (AREA)
Hematology (AREA)
Endocrinology (AREA)
Emergency Medicine (AREA)
Child & Adolescent Psychology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

HUE14802755A 2013-11-14 2014-11-06 Ghrelin O-acyl transferase inhibitory substituted piperidyl ethylpyrimidines HUE035590T2 (en)

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EP13382460		2013-11-14

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US (1)	US9035051B1 (fr)
EP (1)	EP3068775B1 (fr)
JP (1)	JP6159484B2 (fr)
KR (1)	KR101739243B1 (fr)
CN (1)	CN105636948B (fr)
AP (1)	AP2016009189A0 (fr)
AR (1)	AR098274A1 (fr)
AU (1)	AU2014348967B2 (fr)
BR (1)	BR112016009488B1 (fr)
CA (1)	CA2926224C (fr)
CL (1)	CL2016001023A1 (fr)
CR (1)	CR20160184A (fr)
CY (1)	CY1119489T1 (fr)
DK (1)	DK3068775T3 (fr)
DO (1)	DOP2016000070A (fr)
EA (1)	EA028550B1 (fr)
ES (1)	ES2647790T3 (fr)
HR (1)	HRP20171648T1 (fr)
HU (1)	HUE035590T2 (fr)
IL (1)	IL244856A (fr)
JO (1)	JO3302B1 (fr)
LT (1)	LT3068775T (fr)
MA (1)	MA39025B1 (fr)
ME (1)	ME02841B (fr)
MX (1)	MX2016006223A (fr)
NO (1)	NO3068775T3 (fr)
NZ (1)	NZ718373A (fr)
PE (1)	PE20160609A1 (fr)
PH (1)	PH12016500895A1 (fr)
PL (1)	PL3068775T3 (fr)
PT (1)	PT3068775T (fr)
RS (1)	RS56533B1 (fr)
SG (1)	SG11201602953YA (fr)
SI (1)	SI3068775T1 (fr)
TN (1)	TN2016000145A1 (fr)
TW (1)	TWI538677B (fr)
UA (1)	UA118034C2 (fr)
WO (1)	WO2015073281A1 (fr)
ZA (1)	ZA201602202B (fr)

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AR104672A1 (es) *	2015-04-15	2017-08-09	Lilly Co Eli	Inhibidores de grelina o-aciltransferasa
AR104673A1 (es) *	2015-04-15	2017-08-09	Lilly Co Eli	Inhibidores de grelina o-aciltransferasa
JP6651054B2 (ja) *	2016-08-05	2020-02-19	ベーリンガーインゲルハイムインターナショナルゲゼルシャフトミットベシュレンクテルハフツング	グレリンｏ−アシルトランスフェラーゼ（ｇｏａｔ）阻害薬として使用するためのオキサジアゾロピリジン誘導体
CN106478519B (zh) *	2016-10-10	2018-12-11	上海再启生物技术有限公司	一种2-甲基-4-氨基-6-氯嘧啶的制备方法
WO2019149658A1 (fr)	2018-02-02	2019-08-08	Boehringer Ingelheim International Gmbh	Dérivés d'oxadiazolopyridine à substitution pyrazole et indazole destinés à être utilisés en tant qu'inhibiteurs de la ghréline o-acyl transférase (goat)
CA3087826A1 (fr) *	2018-02-02	2019-08-08	Boehringer Ingelheim International Gmbh	Derives d'oxadiazolopyridine a substitution benzyle, (pyridin-3-yl)methyle ou (pyridin-4-yl)methyle utilises en tant qu'inhibiteurs de la ghreline o-acyltransferase (goat)
CR20200331A (es) *	2018-02-02	2020-09-03	Boehringer Ingelheim Int	Derivados de oxadiazolopirisdina sustituidos con heterociclilo para usar como inhibidores de ghrelin o-aciltrasferasa (goat)
JP7083397B2 (ja)	2018-02-02	2022-06-10	ベーリンガーインゲルハイムインターナショナルゲゼルシャフトミットベシュレンクテルハフツング	グレリンｏ－アシルトランスフェラーゼ（ｇｏａｔ）阻害剤として使用するためのトリアゾロピリミジン誘導体
CN108516971A (zh) *	2018-05-30	2018-09-11	王丽萍	一种苯并[b]噻吩类化合物及其在肥胖和糖尿病中的应用
CN108558849A (zh) *	2018-05-30	2018-09-21	王丽萍	一种苯并[b]噻吩类化合物及其在肥胖和糖尿病中的应用
CN108558852A (zh) *	2018-05-30	2018-09-21	王丽萍	一种goat抑制剂及其在肥胖和糖尿病中的应用
CN108774221A (zh) *	2018-05-30	2018-11-09	王丽萍	一种goat抑制剂及其在肥胖和糖尿病中的应用
CN108610337A (zh) *	2018-05-30	2018-10-02	王丽萍	一种苯并[b]噻吩类化合物及其在肥胖和糖尿病中的应用
PH12022552277A1 (en)	2020-02-28	2024-03-04	Kallyope Inc	Gpr40 agonists
PL4153600T3 (pl)	2020-05-22	2024-12-16	Boehringer Ingelheim International Gmbh	Sposób ciągły wytwarzania 7-amino-5-metylo-[1,2,5]oksadiazolo[3,4- b]pirydynokarboksylanu alkilu
WO2021233882A1 (fr)	2020-05-22	2021-11-25	Boehringer Ingelheim International Gmbh	Procédé de fabrication de 7-amino-5-méthyl- [1,2,5] oxadiazolo [3,4-b] pyridine-carboxylate d'alkyle

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* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
JP2003528088A (ja) *	2000-03-23	2003-09-24	メルクエンドカムパニーインコーポレーテッド	メラノコルチン受容体作働薬としての置換ピペリジン類
WO2005026211A2 (fr)	2003-09-05	2005-03-24	Eli Lilly And Company	Anticorps anti-ghreline
EP1776386A1 (fr)	2004-07-14	2007-04-25	Eli Lilly And Company	Anticorps anti-ghreline
CA2587627A1 (fr)	2004-11-15	2006-05-26	Eli Lilly And Company	Anticorps de desacyle ghreline et utilisations therapeutiques de ceux-ci
EP1856154A1 (fr)	2005-02-23	2007-11-21	Eli Lilly And Company	Anticorps anti-ghreline humanises
JP4975739B2 (ja) *	2005-05-17	2012-07-11	シェーリングコーポレイション	脂質異常症の処置のための、ニコチン酸受容体アゴニストとしての複素環
CN101175759A (zh) *	2005-05-17	2008-05-07	先灵公司	作为治疗血脂异常的烟酸受体激动剂的杂环化合物
US20070213359A1 (en) *	2005-12-30	2007-09-13	Acadia Pharmaceuticals Inc.	Bicyclic-nitrogen compounds as modulators of ghrelin receptor and uses thereof
MX2010010241A (es) *	2008-03-20	2010-12-06	Forest Lab Holdings Ltd	Derivados de piperidina novedosos como inhibidores de estearoil-coa desaturasa.
AR091516A1 (es) *	2012-06-22	2015-02-11	Actelion Pharmaceuticals Ltd	Derivados de 1-[m-carboxamido(hetero)aril-metil]-heterociclil-carboxamida

2014
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Also Published As

Publication number	Publication date
LT3068775T (lt)	2017-11-27
EP3068775B1 (fr)	2017-09-06
SI3068775T1 (sl)	2017-10-30
PT3068775T (pt)	2017-11-20
US20150133474A1 (en)	2015-05-14
JP6159484B2 (ja)	2017-07-05
WO2015073281A1 (fr)	2015-05-21
NO3068775T3 (fr)	2018-02-03
BR112016009488B1 (pt)	2021-01-19
TN2016000145A1 (en)	2017-10-06
HK1222860A1 (en)	2017-07-14
MX2016006223A (es)	2016-08-08
NZ718373A (en)	2017-12-22
MA39025B1 (fr)	2018-05-31
ME02841B (fr)	2018-01-20
AP2016009189A0 (en)	2016-05-31
ZA201602202B (en)	2019-10-30
PL3068775T3 (pl)	2018-01-31
US9035051B1 (en)	2015-05-19
EA028550B1 (ru)	2017-11-30
TW201529073A (zh)	2015-08-01
KR101739243B1 (ko)	2017-05-23
TWI538677B (zh)	2016-06-21
AU2014348967B2 (en)	2017-05-04
PH12016500895B1 (en)	2016-06-20
AU2014348967A1 (en)	2016-04-28
DOP2016000070A (es)	2016-05-30
MA39025A1 (fr)	2017-05-31
AR098274A1 (es)	2016-05-18
IL244856A (en)	2017-07-31
CN105636948A (zh)	2016-06-01
CA2926224A1 (fr)	2015-05-21
CA2926224C (fr)	2017-05-02
JP2016537371A (ja)	2016-12-01
RS56533B1 (sr)	2018-02-28
BR112016009488A8 (pt)	2018-01-30
IL244856A0 (en)	2016-05-31
CN105636948B (zh)	2017-10-24
JO3302B1 (ar)	2018-09-16
PH12016500895A1 (en)	2016-06-20
ES2647790T3 (es)	2017-12-26
SG11201602953YA (en)	2016-05-30
UA118034C2 (uk)	2018-11-12
PE20160609A1 (es)	2016-07-03
HRP20171648T1 (hr)	2017-12-15
EP3068775A1 (fr)	2016-09-21
EA201690764A1 (ru)	2016-07-29
KR20160068926A (ko)	2016-06-15
CL2016001023A1 (es)	2016-11-18
CR20160184A (es)	2016-06-17
CY1119489T1 (el)	2018-03-07
DK3068775T3 (en)	2017-10-23

Publication	Publication Date	Title
DK3068775T3 (en)	2017-10-23	SUBSTITUTED PIPERIDYL-ETHYL-PYRIMIDINE AS GHRELIN-O-ACYL TRANSFERASE INHIBITOR
US9108927B2 (en)	2015-08-18	Salts of an epidermal growth factor receptor kinase inhibitor
EP3283473B1 (fr)	2019-01-02	Inhibiteurs de la ghréline o-acyl transférase
EP3283474B1 (fr)	2019-12-18	Inhibiteurs de la ghréline o-acyl transférase
EP2994456A1 (fr)	2016-03-16	Sels d'un inhibiteur de kinases du récepteur du facteur de croissance épidermique
HK1222860B (en)	2018-04-27	Substituted piperidyl-ethyl-pyrimidine as ghrelin o-acyl transferase inhibitor